Parasitic diseases impose a tremendous toll on the global public health. Malaria causes up to 1.24 million deaths every year, while human filariasis remains a major cause of disability in the developing world. We propose to focus on two of the most important causative agents of parasitic disease in the world, the apicomplexan blood parasite Plasmodium falciparum, and the filarial nematode Brugia malayi, which causes lymphatic filariasis. We hypothesize that genomic variation in natural parasite populations and measurable interactions between host, parasites, and the microbiome can be exploited to develop novel strategies for control, treatment, and prevention of malaria and filariasis. The recent emergence and possible spread of artemisinin-resistant falciparum malaria in Southeast Asia threatens to derail malaria elimination efforts, and extensive genetic variation in natural populations of P. falciparum poses a major obstacle to the development of highly efficacious malaria vaccines. To provide new tools for surveillance and containment of drugresistant malaria, we will investigate the genetic basis of reduced susceptibility of P. falciparum to artemisinin antimalarial drugs. We will also identify loci in host and parasite genomes associated with protective naturally acquired immunity to P. falciparum in an effort to establish immune correlates of protection that can inform vaccine development. The characterization of genetic variation in parasite populations at sites where a whole organism vaccine will be tested represents a needed step toward the development of a broadly efficacious malaria vaccine. A new third generation long read sequencing platform will be applied for the first time to sequence and assemble malaria genomes using isolates collected in separately funded field studies. For filariasis, doxycycline is a promising new treatment that can target the adult worms, but more treatment alternatives are needed. We will identify novel filarial drug targets using genome and transcriptome data and examine their functionality and essentiality with RNAi. Because malnutrition is often co-endemic with filariasis, we will also examine the metabolic, transcriptomic, and microbiome response of infected animals kept on micronutrient deficient diets. Genomics, epidemiology, and fundamental research will be integrated in all of these endeavors to improve our understanding of the determinants of disease outcomes and facilitate the development of new tools for the control and elimination of malaria and filariasis.